Spiropyrazole compounds

ABSTRACT

A compound of the formula (I):  
                 
 
     wherein  
     Z, W, A, B, C, R 1 , R 2 , Q and n are as disclosed herein.

[0001] This application claims priority from U.S. ProvisionalApplication Serial No. 60/284,675, filed Apr. 18, 2001, the disclosureof which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] Chronic pain is a major contributor to disability and is thecause of an untold amount of suffering. The successful treatment ofsevere and chronic pain is a primary goal of the physician with opioidanalgesics being preferred drugs.

[0003] Until recently, there was evidence of three major classes ofopioid receptors in the central nervous system (CNS), with each classhaving subtype receptors. These receptor classes were designated as μ, δand κ. As opiates had a high affinity to these receptors while not beingendogenous to the body, research followed in order to identify andisolate the endogenous ligands to these receptors. These ligands wereidentified as enkephalins, endorphins and dynorphins.

[0004] Recent experimentation has led to the identification of a cDNAencoding an opioid receptor-like (ORL1) receptor with a high degree ofhomology to the known receptor classes. This newly discovered receptorwas classified as an opioid receptor based only on structural grounds,as the receptor did not exhibit pharmacological homology. It wasinitially demonstrated that non-selective ligands having a high affinityfor μ, δ and κ receptors had low affinity for the ORL1. Thischaracteristic, along with the fact that an endogenous ligand had notyet been discovered, led to the term “orphan receptor”.

[0005] Subsequent research led to the isolation and structure of theendogenous ligand of the ORL1 receptor. This ligand is a seventeen aminoacid peptide structurally similar to members of the opioid peptidefamily.

[0006] The discovery of the ORL1 receptor presents an opportunity indrug discovery for novel compounds which can be administered for painmanagement or other syndromes modulated by this receptor.

[0007] All documents cited herein, including the foregoing, areincorporated by reference in their entireties for all purposes.

OBJECTS AND SUMMARY OF THE INVENTION

[0008] It is accordingly an object of certain embodiments of the presentinvention to provide new compounds which exhibit affinity for the ORL1receptor.

[0009] It is an object of certain embodiments of the present inventionto provide new compounds which exhibit affinity for the ORL1 receptorand one or more of the μ, δ or κ receptors.

[0010] It is an object of certain embodiments of the present inventionto provide new compounds for treating a patient suffering from chronicor acute pain by administering a compound having affinity for the ORL1receptor.

[0011] It is an object of certain embodiments of the present inventionto provide new compounds which have agonist activity at the μ, δ and κreceptors which is greater than compounds currently available e.g.morphine.

[0012] It is an object of certain embodiments of the present inventionto provide methods of treating chronic and acute pain by administeringcompounds which have agonist activity at the μ, δ and κ receptors whichis greater than compounds currently available.

[0013] It is an object of certain embodiments of the present inventionto provide methods of treating chronic and acute pain by administeringnon-opioid compounds which have agonist activity at the μ, δ and κreceptors and which produce less side effects than compounds currentlyavailable.

[0014] It is an object of certain embodiments of the present inventionto provide compounds useful as analgesics, anti-inflammatories,diuretics, anesthetics and neuroprotective agents, anti-hypertensives,anti-anxioltics; agents for appetite control; hearing regulators;anti-tussives, anti-asthmatics, modulators of locomotor activity,modulators of learning and memory, regulators of neurotransmitter andhormone release, kidney function modulators, anti-depressants, agents totreat memory loss due to Alzheimer's disease or other dementias,anti-epileptics, anti-convulsants, agents to treat withdrawal fromalcohol and drugs of addiction, agents to control water balance, agentsto control sodium excretion and agents to control arterial bloodpressure disorders and methods for administering said compounds.

[0015] The compounds of the present invention are useful for modulatinga pharmacodynamic response from one or more opioid receptors (ORL-1, μ,δ and κ) centrally and/or peripherally. The response can be attributedto the compound stimulating (agonist) or inhibiting (antagonist) the oneor more receptors. Certain compounds can stimulate one receptor (e.g., aμ agonist) and inhibit a different receptor (e.g., an ORL-1 antagonist).

[0016] Other objects and advantages of the present invention will becomeapparent from the following detailed description thereof. The presentinvention in certain embodiments comprises compounds having the generalformula (I):

[0017] wherein W is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkylsubstituted with 1-3 halogen, C₃₋₁₂ cycloalkyl substituted with 1-3halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl-substituted with 1-3 halogen, C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂ cycloalkoxy-substituted with1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-,hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀cyanoC₃₋₁₀cycloalkyl-, —CON(V₁)₂,NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-,diaminoalkyl-, -sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a6-membered heteroaromatic ring, a 6-membered heterocyclicC₁₋₄alkyl-, a6-membered heteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a6-membered aromaticC₁₋₄ alkyl-, a 5-membered heterocyclic ringoptionally substituted with an oxo or thio, a 5-membered heteroaromaticring, a 5-membered heterocyclicC₁₋₄alkyl-optionally substituted with anoxo or thio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅(═NH)W₁, —C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, whereinW₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, —CH₂OH, amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a5-membered heteroaromatic ring optionally substituted with 1-3 loweralkyl;

[0018] wherein each V₁ is independently selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, benzyl and phenyl;

[0019] Q is a C₁₋₈ alkyl, 5-8 membered cycloalkyl, 5-8 memberedheterocyclic or a 6 membered aromatic or heteroaromatic group;

[0020] n is an integer from 0 to 3;

[0021] A, B and C are independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂,hydroxyC₁₋₁₀alkyl-, aminocarbonyl-, C₁₋₄alkylaminocarbonyl-,diC₁₋₄alkylaminocarbonyl-, acylamino-, acylaminoalkyl-, amide,sulfonylaminoC₁₋₁₀alkyl-, or A-B can together form a C₂₋₆ bridge, or B—Ccan together form a C₃₋₇ bridge, or A-C can together form a C₁₋₅ bridge;

[0022] Z is selected from the group consisting of a bond, straight orbranched C₁₋₆ alkylene, —NH—, —CH₂O—, —CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—,—CH₂CONH—, —NHCH₂CO—, —CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, —O—and —HC═CH—, wherein the carbon and/or nitrogen atoms are unsubstitutedor substituted with one or more lower alkyl, hydroxy, halo or alkoxygroup;

[0023] R₁ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino-,C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁, cyano, cyanoC₁₋₁₀alkyl-,cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-,aminocarbonyl-, C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-,benzyl, C₃₋₁₂ cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl orheteroaryl ring, a hetero-monocyclic ring, a hetero-bicyclic ringsystem, and a spiro ring system of the formula (II):

[0024] wherein X₁ and X₂ are independently selected from the groupconsisting of NH, O, S and CH₂; and wherein said alkyl, cycloalkyl,alkenyl, C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ isoptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro,trifluoromethyl-, cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-,—C₁₋₅(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-memberedheteroaromaticC₀₋₄alkyl-, phenyl, benzyl, benzyloxy, said phenyl,benzyl, and benzyloxy optionally being substituted with 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀alkoxy-, and cyano; and wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkenyl, monocyclic, bicyclic or tricyclic aryl, heteroaryl ring,hetero-monocyclic ring, hetero-bicyclic ring system, or spiro ringsystem of the formula (II) is optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, nitro, trifluoromethyl-, phenyl, benzyl, phenyloxy andbenzyloxy, wherein said phenyl, benzyl, phenyloxy or benzyloxy isoptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, and cyano;

[0025] R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl- and halogen, said alkyl or cycloalkyloptionally substituted with an oxo, amino, alkylamino or dialkylaminogroup;

[0026] and pharmaceutically acceptable salts thereof and solvatesthereof.

[0027] The present invention in certain embodiments comprises compoundshaving the gerneral formula (IA)

[0028] wherein

[0029] n is an integer from 0 to 3;

[0030] Z is selected from the group consisting of a bond, —CH₂—, —NH—,—CH₂O—, —CH₂CH₂—CH₂NH—, —CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—,—CH₂CO—, —COCH₂—, —CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—, wherein thecarbon and/or nitrogen atoms are unsubstituted or substituted with alower alkyl, halogen, hydroxy or alkoxy group;

[0031] R₁ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl,C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl, amino, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂ cycloalkenyl, a monocyclic, bicyclicor tricyclic aryl or heteroaryl ring, a hetero-monocyclic ring, ahetero-bicyclic ring system, and a spiro ring system of the formula(II):

[0032] wherein X₁ and X₂ are independently selected from the groupconsisting of NH, O, S and CH₂;

[0033] wherein said monocyclic aryl is preferably phenyl;

[0034] wherein said bicyclic aryl is preferably naphthyl;

[0035] wherein said alkyl, cycloalkyl, alkenyl, C₁₋₁₀alkylamino,C₃₋₁₂cycloalkylamino, or benzyl is optionally substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano, phenyl, benzyl, benzyloxy,said phenyl, benzyl, and benzyloxy optionally being substituted with 1-3substituents selected from the group consisting of halogen, C₁₋₁₀ alkyl,C₁₋₁₀ alkoxy, and cyano;

[0036] wherein said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic,bicyclic or tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, and spiro ring system of the formula (II)are optionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀alkoxy, nitro, trifluoromethyl,phenyl, benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl,phenyloxy and benzyloxy are optionally substituted with 1-3 substituentsselected from the group consisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, and cyano;

[0037] R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl and halogen, said alkyl optionally substitutedwith an oxo group;

[0038] and pharmaceutically acceptable salts thereof and solvatesthereof.

[0039] In certain preferred embodiments of formula (I), Q is phenyl or a6 membered heteroaromatic group containing 1-3 nitrogen atoms.

[0040] In certain preferred embodiments of formula (I) or (IA), the R₁alkyl is methyl, ethyl, propyl, butyl, pentyl, or hexyl.

[0041] In certain preferred embodiments of formula (I) or (IA), the R₁cycloalkyl is cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, or norbornyl.

[0042] In other preferred embodiments of formula (I) or (IA), the R₁bicyclic ring system is naphthyl. In other preferred embodiments offormula (I) or (IA), the R₁ bicyclic ring system is tetrahydronaphthyl,or decahydronaphthyl and the R₁ tricyclic ring system isdibenzocycloheptyl. In other preferred embodiments R₁ is phenyl orbenzyl.

[0043] In other preferred embodiments of formula (I) or (IA), the R₁bicyclic aromatic ring is a 10-membered ring, preferably quinoline ornaphthyl.

[0044] In other preferred embodiments of formula (I) or (IA), the R₁bicyclic aromatic ring is a 9-membered ring, preferably indenyl.

[0045] In certain embodiments of formula (I) or (IA), Z is a bond,methyl, or ethyl.

[0046] In certain embodiments of formula (I) or (IA), the Z group ismaximally substituted as not to have any hydrogen substitution on thebase Z group. For example, if the base Z group is —CH₂—, substitutionwith two methyl groups would remove hydrogens from the —CH₂— base Zgroup.

[0047] In other preferred embodiments of formula (I) or (IA), n is 0.

[0048] In certain embodiments of formula (I) or (IA), X₁ and X₂ are bothO.

[0049] In certain embodiments of formula (I), W is —CH₂C═ONH₂,—C(NH)NH₂, pyridylmethyl, cyclopentyl, cyclohexyl, furanylmethyl,—C═OCH₃, —CH₂CH₂NHC═OCH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃, furanylcarbonyl-,methylpyrrolylcarbonyl-, diazolecarbonyl-, azolemethyl-,trifluoroethyl-, hydroxyethyl-, cyanomethyl-, oxo-oxazolemethyl-, ordiazolemethyl-.

[0050] In certain embodiments of formula (I), ZR₁ is cyclohexylethyl-,cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-,phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-,pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-,tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-,thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-,isopropoxybutyl-, hexyl-, or oxocanylpropyl-.

[0051] In certain embodiments of formula (I), at least one of ZR₁ or Wis —CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-,NH₂SOmethyl-, aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, ordiC₁₋₄alkylaminocarbonylmethyl-.

[0052] In certain embodiments of formula (I), ZR₁ is 3,3 diphenylpropyloptionally substituted at the 3 carbon of the propyl with —COOV₁,tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-, C₁₋₄alkylaminocarbonyl-,or diC₁₋₄alkylaminocarbonyl-.

[0053] In alternate embodiments of formula (I) or (IA), ZR₁ can be

[0054] wherein

[0055] Y₁ is R₃—(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl,R₆—(C₃-C₁₂)cyclo-alkyl, R₇—(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CNor —C(O)NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; orY₁, Y₂ and Y₃, together with the carbon to which they are attached, formone of the following structures:

[0056] wherein r is 0 to 3; w and u are each 0-3, provided that the sumof w and u is 1-3; c and d are independently 1 or 2; s is 1 to 5; andring E is a fused R₄-phenyl or R₅-heteroaryl ring;

[0057] R₁₀ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ and—(C₁-C₆)alkyl-NR₈R₉;

[0058] R₁₁ is 1 to 3 substituents independently selected from the groupconsisting of R₁₀, —CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents onadjacent ring carbon atoms may together form a methylenedioxy orethylenedioxy ring;

[0059] R₈ and R₉ are independently selected from the group consisting ofhydrogen, (C₁-C₆)alkyl, (C₃-C₁₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl;

[0060] R₃ is 1 to 3 substituents independently selected from the groupconsisting of H, R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈ R₉, —OR₁₂ and —S(O)₀₋₂R₁₂;

[0061] R₆ is 1 to 3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂;

[0062] R₄ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉,—(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —SO₂R₈, ——SOR₈, —SR₈, —NO₂,—CONR₈R₉, —NR₉COR₈, —COR₈, —COCF₃, —OCOR₈, —OCO₂R₈, —COOR₈,—(C₁-C₆)alkyl-NHCOOC(CH₃)₃, —(C₁-C₆)alkyl-NHCOCF₃,—(C₁-C₆)alkyl-NHSO₂—(C₁-C₆)alkyl, —(C₁-C₆)alkyl-NHCONH—(C₁-C₆)-alkyl and

[0063] wherein f is 0 to 6; or R₄ substituents on adjacent ring carbonatoms may together form a methylenedioxy or ethylenedioxy ring;

[0064] R₅ is 1 to 3 substituents independently selected from the groupconsisting of hydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl,(C₃-C₁₂)cycloalkyl, —CN, —CF₃, —OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃,—NR₈R₉,—(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈, —SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈,—COR₈, —OCOR₈, —OCO₂R₈ and —COOR₈;

[0065] R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ or—(C₁-C₆)alkyl-NR₈R₉;

[0066] R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈,—(C₁-C₆)alkyl-NR₈R₉, —(C₁-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl;

[0067] R₁₃ is 1-3 substituents independently selected from the groupconsisting of H, (C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo;

[0068] R₁₄ is independently selected from the group consisting of H,(C₁-C₆)alkyl and R₁₃—C₆H₄—CH₂—.

[0069] As used herein, the term “alkyl” means a linear or branchedsaturated aliphatic hydrocarbon group having a single radical and 1-10carbon atoms. Examples of alkyl groups include methyl, propyl,isopropyl, butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and pentyl.A branched alkyl means that one or more alkyl groups such as methyl,ethyl or propyl, replace one or both hydrogens in a —CH₂— group of alinear alkyl chain. The term “lower alkyl” means an alkyl of 1-3 carbonatoms.

[0070] The term “alkoxy” means an “alkyl” as defined above connected toan oxygen radical.

[0071] The term “cycloalkyl” means a non-aromatic mono- or multicyclichydrocarbon ring system having a single radical and 3-12 carbon atoms.Exemplary monocyclic cycloalkyl rings include cyclopropyl, cyclopentyl,and cyclohexyl. Exemplary multicyclic cycloalkyl rings include adamantyland norbornyl.

[0072] The term “alkenyl” means a linear or branched aliphatichydrocarbon group containing a carbon-carbon double bond having a singleradical and 2-10 carbon atoms.

[0073] A “branched” alkenyl means that one or more alkyl groups such asmethyl, ethyl or propyl replace one or both hydrogens in a —CH₂— or —CH═linear alkenyl chain. Exemplary alkenyl groups include ethenyl, 1- and2-propenyl, 1-, 2- and 3-butenyl, 3-methylbut-2-enyl, 2-propenyl,heptenyl, octenyl and decenyl.

[0074] The term “cycloalkenyl” means a non-aromatic monocyclic ormulticyclic hydrocarbon ring system containing a carbon-carbon doublebond having a single radical and 3 to 12 carbon atoms. Exemplarymonocyclic cycloalkenyl rings include cyclopropenyl, cyclopentenyl,cyclohexenyl or cycloheptenyl. An exemplary multicyclic cycloalkenylring is norbornenyl.

[0075] The term “aryl” means a carbocyclic aromatic ring systemcontaining one, two or three rings which may be attached together in apendent manner or fused, and containing a single radical. Exemplary arylgroups include phenyl, naphthyl and acenaphthyl.

[0076] The term “heterocyclic” means cyclic compounds having one or moreheteroatoms (atoms other than carbon) in the ring, and having a singleradical. The ring may be saturated, partially saturated or unsaturated,and the heteroatoms may be selected from the group consisting ofnitrogen, sulfur and oxygen. Examples of saturated heterocyclic radicalsinclude saturated 3 to 6-membered hetero-monocyclic groups containing 1to 4 nitrogen atoms, such as pyrrolidinyl, imidazolidinyl, piperidino,piperazinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asmorpholinyl; saturated 3- to 6-membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolidinyl. Examples of partially saturated heterocyclic radicalsinclude dihydrothiophene, dihydropyran, and dihydrofuran. Otherheterocyclic groups can be 7 to 10 carbon rings substituted withheteroatoms such as oxocanyl and thiocanyl. When the heteroatom issulfur, the sulfur can be a sulfur dioxide such as thiocanyldioxide.

[0077] The term “heteroaryl” means unsaturated heterocyclic radicals,wherein “heterocyclic” is as previously described. Exemplary heteroarylgroups include unsaturated 3 to 6 membered hetero-monocyclic groupscontaining 1 to 4 nitrogen atoms, such as pyrrolyl, pyridyl, pyrimidyl,and pyrazinyl; unsaturated condensed heterocyclic groups containing 1 to5 nitrogen atoms, such as indolyl, quinolyl and isoquinolyl; unsaturated3 to 6-membered hetero-monocyclic groups containing an oxygen atom, suchas furyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining a sulfur atom, such as thienyl; unsaturated 3 to 6 memberedhetero-monocyclic groups containing 1 to 2 oxygen atoms and 1 to 3nitrogen atoms, such as oxazolyl; unsaturated condensed heterocyclicgroups containing 1 to 2 oxygen atoms and 1 to 3 nitrogen atoms, such asbenzoxazolyl; unsaturated 3 to 6 membered hetero-monocyclic groupscontaining 1 to 2 sulfur atoms and 1 to 3 nitrogen atoms, such asthiazolyl; and unsaturated condensed heterocyclic group containing 1 to2 sulfur atoms and 1 to 3 nitrogen atoms, such as benzothiazolyl. Theterm “heteroaryl” also includes unsaturated heterocyclic radicals,wherein “heterocyclic” is as previously described, in which theheterocyclic group is fused with an aryl group, in which aryl is aspreviously described. Exemplary fused radicals include benzofuran,benzdioxole and benzothiophene.

[0078] As used herein, the term “heterocyclicC₁₋₄alkyl”,“heteroaromaticC₁₋₄alkyl” and the like refer to the ring structurebonded to a C₁₋₄ alkyl radical.

[0079] All of the cyclic ring structures disclosed herein can beattached at any point where such connection is possible, as recognizedby one skilled in the art.

[0080] As used herein, the term “patient” includes a human or an animalsuch as a companion animal or livestock.

[0081] As used herein, the term “halogen” includes fluoride, bromide,chloride, iodide or alabamide.

[0082] The invention disclosed herein is meant to encompass allpharmaceutically acceptable salts thereof of the disclosed compounds.The pharmaceutically acceptable salts include, but are not limited to,metal salts such as sodium salt, potassium salt, cesium salt and thelike; alkaline earth metals such as calcium salt, magnesium salt and thelike; organic amine salts such as triethylamine salt, pyridine salt,picoline salt, ethanolamine salt, triethanolaminie salt,dicyclohexylamine salt, N,N′-dibenzylethylenediamine salt and the like;inorganic acid salts such as hydrochloride, hydrobromide, sulfate,phosphate and the like; organic acid salts such as formate, acetate,trifluoroacetate, maleate, fumarate, tartrate and the like; sulfonatessuch as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and thelike; amino acid salts such as arginate, asparginate, glutamate and thelike.

[0083] The invention disclosed herein is also meant to encompass allprodrugs of the disclosed compounds. Prodrugs are considered to be anycovalently bonded carriers which release the active parent drug in vivo.

[0084] The invention disclosed herein is also meant to encompass the invivo metabolic products of the disclosed compounds. Such products mayresult for example from the oxidation, reduction, hydrolysis, amidation,esterification and the like of the administered compound, primarily dueto enzymatic processes. Accordingly, the invention includes compoundsproduced by a process comprising contacting a compound of this inventionwith a mammal for a period of time sufficient to yield a metabolicproduct thereof. Such products typically are identified by preparing aradiolabelled compound of the invention, administering it parenterallyin a detectable dose to an animal such as rat, mouse, guinea pig,monkey, or to man, allowing sufficient time for metabolism to occur andisolating its conversion products from the urine, blood or otherbiological samples.

[0085] The invention disclosed herein is also meant to encompass thedisclosed compounds being isotopically-labelled by having one or moreatoms replaced by an atom having a different atomic mass or mass number.Examples of isotopes that can be incorporated into the disclosedcompounds include isotopes of hydrogen, carbon, nitrogen, oxygen,phosphorous, fluorine and chlorine, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O,¹⁷, ³¹P, ³²P, ³⁵S, ¹⁸F, and ³⁶Cl, respectively. Some of the compoundsdisclosed herein may contain one or more asymmetric centers and may thusgive rise to enantiomers, diastereomers, and other stereoisomeric forms.The present invention is also meant to encompass all such possible formsas well as their racemic and resolved forms and mixtures thereof. Whenthe compounds described herein contain olefinic double bonds or othercenters of geometric asymmetry, and unless specified otherwise, it isintended to include both E and Z geometric isomers. All tautomers areintended to be encompassed by the present invention as well

[0086] As used herein, the term “stereoisomers” is a general term forall isomers of individual molecules that differ only in the orientationof their atoms in space. It includes enantiomers and isomers ofcompounds with more than one chiral center that are not mirror images ofone another (diastereomers).

[0087] The term “chiral center” refers to a carbon atom to which fourdifferent groups are attached.

[0088] The term “enanitiomer” or “enantiomeric” refers to a moleculethat is nonsuperimposeable on its mirror image and hence opticallyactive wherein the enantiomer rotates the plane of polarized light inone direction and its mirror image rotates the plane of polarized lightin the opposite direction.

[0089] The term “racemic” refers to a mixture of equal parts ofenantiomers and which is optically inactive.

[0090] The term “resolution” refers to the separation or concentrationor depletion of one of the two enantiomeric forms of a molecule.

[0091] The term “modulate” as used herein with respect to the ORL-1receptor means the mediation of a pharmacodynamic response (e.g.,analgesia) in a subject from (i) inhibiting or activating the receptor,or (ii) directly or indirectly affecting the normal regulation of thereceptor activity. Compounds which modulate the receptor activityinclude agonists, antagonists, mixed agonists/antagonists and compoundswhich directly or indirectly affect regulation of the receptor activity.

[0092] Certain preferred compounds of the invention include:

[0093]8-(4-propylcyclohexyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0094] 8-(5-methylhex-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0095] 8-norbornyl-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0096]8-(decahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0097] 8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0098]8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0099]8-[4-(2-propyl)-cyclohexyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0100]8-(1,3-dihydroinden-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0101]8-[(naphth-2-yl-methyl)]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0102] 8-(p-phenylbenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0103]8-[4,4-Bis(4-fluorophenyl)butyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0104] 8-(benzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0105]8-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0106]8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0107] 8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;

[0108] 8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;and

[0109] pharmaceutically acceptable salts thereof and solvates thereof.

[0110] Another preferred compound is8-(acenaphthen-9-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one andpharmaceutically acceptable salts thereof and solvates thereof.

[0111] The present invention also provides use of any of the disclosedcompounds in the preparation of a medicament for treating pain and otherdisease states modulated by an opioid receptor, e.g., the ORL-1receptor.

DETAILED DESCRIPTION OF THE INVENTION

[0112] The compounds of the present invention can be administered toanyone requiring modulation of the opioid and ORL1 receptors.Administration may be orally, topically, by suppository, inhalation, orparenterally.

[0113] The present invention also encompasses all pharmaceuticallyacceptable salts of the foregoing compounds. One skilled in the art willrecognize that acid addition salts of the presently claimed compoundsmay be prepared by reaction of the compounds with the appropriate acidvia a variety of known methods.

[0114] Various oral dosage forms can be used, including such solid formsas tablets, gelcaps, capsules, caplets, granules, lozenges and bulkpowders and liquid forms such as emulsions, solution and suspensions.The compounds of the present invention can be administered alone or canbe combined with various pharmaceutically acceptable carriers andexcipients known to those skilled in the art, including but not limitedto diluents, suspending agents, solubilizers, binders, disintegrants,preservatives, coloring agents, lubricants and the like.

[0115] When the compounds of the present invention are incorporated intooral tablets, such tablets can be compressed, tablet triturates,enteric-coated, sugar-coated, film-coated, multiply compressed ormultiply layered. Liquid oral dosage forms include aqueous andnonaqueous solutions, emulsions, suspensions, and solutions and/orsuspensions reconstituted from non-effervescent granules, containingsuitable solvents, preservatives, emulsifying agents, suspending agents,diluents, sweeteners, coloring agents, and flavoring agents. When thecompounds of the present invention are to be injected parenterally, theymay be, e.g., in the form of an isotonic sterile solution.Alternatively, when the compounds of the present invention are to beinhaled, they may be formulated into a dry aerosol or may be formulatedinto an aqueous or partially aqueous solution.

[0116] In addition, when the compounds of the present invention areincorporated into oral dosage forms, it is contemplated that such dosageforms may provide an immediate release of the compound in thegastrointestinal tract, or alternatively may provide a controlled and/orsustained release through the gastrointestinal tract. A wide variety ofcontrolled and/or sustained release formulations are well known to thoseskilled in the art, and are contemplated for use in connection with theformulations of the present invention. The controlled and/or sustainedrelease may be provided by, e.g., a coating on the oral dosage form orby incorporating the compound(s) of the invention into a controlledand/or sustained release matrix.

[0117] Specific examples of pharmaceutically acceptable carriers andexcipients that may be used to formulate oral dosage forms, aredescribed in the Handbook of Pharmaceutical Excipients, AmericanPharmaceutical Association (1986). Techniques and compositions formaking solid oral dosage forms are described in Pharmaceutical DosageForms: Tablets (Lieberman, Lachman and Schwartz, editors) 2nd edition,published by Marcel Dekker, Inc. Techniques and compositions for makingtablets (compressed and molded), capsules (hard and soft gelatin) andpills are also described in Remington's Pharmaceutical Sciences (ArthurOsol, editor), 1553B1593 (1980). Techniques and composition for makingliquid oral dosage forms are described in Pharmaceutical Dosage Forms:Disperse Systems, (Lieberman, Rieger and Banker, editors) published byMarcel Dekker, Inc.

[0118] When the compounds of the present invention are incorporated forparenteral administration by injection (e.g., continuous infusion orbolus injection), the formulation for parenteral administration may bein the form of suspensions, solutions, emulsions in oily or aqueousvehicles, and such formulations may further comprise pharmaceuticallynecessary additives such as stabilizing agents, suspending agents,dispersing agents, and the like. The compounds of the invention may alsobe in the form of a powder for reconstitution as an injectableformulation.

[0119] In certain embodiments, the compounds of the present inventioncan be used in combination with at least one other therapeutic agent.Therapeutic agents include, but are not limited to, μ-opioid agonists;non-opioid analgesics; non-steroid antiinflammatory agents; Cox-IIinhibitors; antiemetics; β-adrenergic blockers; anticonvulsants;antidepressants; Ca2+-channel blockers; anticancer agent and mixturesthereof.

[0120] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination with aμ-opioid agonist. μ-opioid agonists, which may be included in theformulations of the present invention include but are not limited toinclude alfentanil, allylprodine, alphaprodine, anileridinebenzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene,codeine, desomorphine, dextromoramide, dezocine, diampromide,diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol,dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone,eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine,etonitazene fentanyl, heroin, hydrocodone, hydromorphone,hydroxypethidine, isomethadone, ketobemidone, levorphanol,levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine,methadone, metopon, morphine, myrophine, nalbuphine, narceine,nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine,norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine,phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,piritramide, proheptazine, promedol, properidine, propiram,propoxyphene, sufentanil, tilidine, tramadol, pharmaceuticallyacceptable salts thereof, and mixtures thereof.

[0121] In certain preferred embodiments, the μ-opioid agonist isselected from codeine, hydromorphone, hydrocodone, oxycodone,dihydrocodeine, dihydromorphine, morphine, tramadol, oxymorphone,pharmaceutically acceptable salts thereof, and mixtures thereof.

[0122] In another embodiment of the invention, the medicament comprisesa mixture of a Cox-II inhibitor and an inhibitor of 5-lipoxygenase forthe treatment of pain and/or inflammation. Suitable Cox-II inhibitorsand 5-lipoxygenase inhibitors, as well as combinations thereof aredescribed in U.S. Pat. No. 6,136,839, which is hereby incorporated byreference in its entirety. Cox-II inhibitors include, but are notlimited to rofecoxib (Vioxx), celecoxib (Celebrex), DUP-697, flosulide,meloxicam, 6-MNA, L-745337, nabumetone, nimesulide, NS-398, SC-5766,T-614, L-768277, GR-253035, JTE-522, RS-57067-000, SC-58125, SC-078,PD-138387,NS-398, flosulide, D-1367, SC-5766, 5766, PD-164387,etoricoxib, valdecoxib and parecoxib or pharmaceutically acceptablesalts, enanitiomers or tautomers thereof.

[0123] The compounds of the present invention can also be combined indosage forms with non-opioid analgesics, e.g., non-steroidalanti-inflammatory agents, including aspirin, ibuprofen, diclofenac,naproxen, benoxaprofen, flurbiprofen, fenoprofen, flubufen, ketoprofen,indoprofen, piroprofen, carprofen, oxaprozin, pramoprofen, muroprofen,trioxaprofen, suprofen, aminoprofen, tiaprofenic acid, fluprofen,bucloxic acid, indomethacin, sulindac, tolmetin, zomepirac, tiopinac,zidometacin, acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,meclofenamic acid, flufenamic acid, niflumic acid tolfenamic acid,diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam,pharmaceutically acceptable salts thereof, and mixtures thereof. Othersuitable non-opioid analgesics which may be included in the dosage formsof the present invention include the following, non-limiting, chemicalclasses of analgesic, antipyretic, nonsteroidal antifinflammatory drugs:salicylic acid derivatives, including aspirin, sodium salicylate,choline magnesium trisalicylate, salsalate, diflunisal, salicylsalicylicacid, sulfasalazine, and olsalazin; para-aminophennol derivativesincluding acetaminophen; indole and indene acetic acids, includingindomethacin, sulindac, and etodolac; heteroaryl acetic acids, includingtolmetin, diclofenac, and ketorolac; anthranilic acids (fenamates),including mefenamic acid, and meclofenamic acid; enolic acids, includingoxicams (piroxicam, tenoxicam), and pyrazolidinediones (phenylbutazone,oxyphenthartazone); and alkanones, including nabumetone. For a moredetailed description of the NSAIDs that may be included within themedicaments employed in the present invention, see Paul A. InselAnalgesic-Antipyretic and Antiinflammatory Agents and Drugs Employed inthe treatment of Gout in Goodman & Gilman's The Pharmacological Basis ofTherapeutics, 617-57 (Perry B. Molinhoff and Raymond W. Ruddon, Eds.,Ninth Edition, 1996), and Glen R. Hanson Analgesic, Antipyretic andAnit-Inflammatory Drugs in Remington: The Science and Practice ofPharmacy Vol II, 1196-1221 (A. R. Gennaro, Ed. 19th Ed. 1995) which arehereby incorporated by reference in their entireties.

[0124] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withantimigraine agents. Antimigraine agents include, but are not limitedto, alpiropride, dihydroergotamine, dolasetron, ergocornine,ergocorninine, ergocryptine, ergot, ergotamine, flumedroxone acetate,fonazine, lisuride, lomerizine, methysergide oxetorone, pizotyline, andmixtures thereof.

[0125] The other therapeutic agent can also be an adjuvant to reduce anypotential side effects such as, for example, an antiemetic agent.Suitable antiemetic agents include, but are not limited to,metoclopromide, domperidone, prochlorperazine, promethazine,chlorpromazine, trimethobenzamide, ondansetron, granisetron,hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron,benzquinamide, bietanautine, bromopride, buclizine, clebopride,cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine,methallatal, metopimazine, nabilone, oxyperndyl, pipamazine,scopolamine, sulpiride, tetrahydrocannabinols, thiethylperazine,thioproperazine, tropisetron, and mixtures thereof.

[0126] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withβ-adrenergic blockers. Suitable β-adrenergic blockers include, but arenot limited to, acebutolol, alprenolol, amosulabol, arotinolol,atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol,bucumolol, bufetolol, bufuralol, bunitrolol, bupranolol, butidrinehydrochloride, butofilolol, carazolol, carteolol, carvedilol,celiprolol, cetamolol, cloranolol, dilevalol, epanolol, esmolol,indenolol, labetalol, levobunolol, mepindolol, metipranolol, metoprolol,moprolol, nadolol, nadoxolol, nebivalol, nifenalol, nipradilol,oxprenolol, penbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sulfinalol, talinolol, tertatolol, tilisolol, timolol,toliprolol, and xibenolol.

[0127] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withanticonvulsants. Suitable anticonvulsants include, but are not limitedto, acetylpheneturide, albutoin, aloxidone, aminoglutethimide,4-amino-3-hydroxybutyric acid, atrolactamide, beclamide, buramate,calcium bromide, carbamazepine, cinromide, clomethiazole, clonazepam,decimemide, diethadione, dimethadione, doxenitroin, eterobarb,ethadione, ethosuximide, ethotoin, felbamate, fluoresone, gabapentin,5-hydroxytryptophan, lamotrigine, magnesium bromide, magnesium sulfate,mephenytoin, mephobarbital, metharbital, methetoin, methsuximide,5-methyl-5-(3-phenanthryl)-hydanitoin, 3-methyl-5-phenylhydantoin,narcobarbital, nimetazepam, nitrazepam, oxcarbazepine, paramethadione,phenacemide, phenetharbital, pheneturide, phenobarbital, phensuximide,phenylmethylbarbituric acid, phenytoin, phethenylate sodium, potassiumbromide, pregabaline, primidone, progabide, sodium bromide, solanum,strontium bromide, suclofenide, sulthiame, tetrantoin, tiagabine,topiramate, trimethadione, valproic acid, valpromide, vigabatrin, andzonisamide.

[0128] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withantidepressants. Suitable antidepressants include, but are not limitedto, binedaline, caroxazone, citalopram, dimethazan, fencamine,indalpine, indeloxazine hydrocholoride, nefopam, nomifensine,oxitriptan, oxypertine, paroxetine, sertraline, thiazesim, trazodone,benmoxine, iproclozide, iproniazid, isocarboxazid, nialamide, octamoxin,phenelzine, cotininie, rolicyprine, rolipram, maprotiline, metralindole,mianserin, mirtazepine, adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine N-oxide, iprindole, lofepramine, melitracen, metapramine,nortriptyline, noxiptilin, opipramol, pizotyline, propizepine,protriptyline, quinupramine, tianeptine, trimipramine, adrafinil,benactyzine, bupropion, butacetin, dioxadrol, duloxetine, etoperidone,febarbamate, femoxetine, fenpentadiol, fluoxetine, fluvoxamine,hematoporphyrin, hypericin, levophacetoperane, medifoxamine,milnacipran, minaprine, mnoclobemide, nefazodone, oxaflozane,piberaline, prolintane, pyrisuccideanol, ritanserin, roxindole, rubidiumchloride, sulpiride, tandospirone, thozalinone, tofenacin, toloxatone,tranylcypromine, L-tryptophan, venlafaxine, viloxazine, and zimeldine.

[0129] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withCa2+-channel blockers. Suitable Ca2+-channel blockers include, but arenot limited to, bepridil, clentiazem, diltiazem, fendiline, gallopamil,mibefradil, prenylamine, semotiadil, terodiline, verapamil, amlodipine,aranidipine, barnidipine, benidipine, cilnidipine, efonidipine,elgodipine, felodipine, isradipine, lacidipine, lercanidipine,manidipine, nicardipine, nifedipine, nilvadipine, nimodipine,nisoldipine, nitrendipine, cinnarizine, flunarizine, lidoflazine,lomerizine, bencyclane, etafenone, fantofarone, and perhexiline.

[0130] In certain embodiments, the compounds of the present inventioncan be formulated in a pharmaceutical dosage form in combination withanticancer agents. Suitable anticancer agents include, but are notlimited to, acivicin; aclarubicin; acodazole hydrochloride; acronine;adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate;aminioglutethimide; amsacrine; anastrozole; anthramycin; asparaginase;asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa;bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin;bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidoone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; interleukin II (includingrecombinant interleukin II, or rIL2), interferon alfa-2a; interferonalfa-2b; interferon alfa-n1; interferon alfa-n3; interferon beta-Ia;interferon gamma-Ib; iproplatin; irinotecan hydrochloride; lanreotideacetate; letrozole; leuprolide acetate; liarozole hydrochloride;lometrexol sodium; lomustine; losoxantrone hydrochloride; masoprocol;maytansine; mechlorethamine hydrochloride; megestrol acetate;melengestrol acetate; melphalan; menogaril; mercaptopurine;methotrexate; methotrexate sodium; metoprine; meturedepa; mitindomide;mitocarcin; mitocromin; mitogillin; mitomalcin; mitomycin; mitosper;mitotane; mitoxantrone hydrochloride; mycophenolic acid; nocodazole;nogalamycin; ormaplatin; oxisuran; paclitaxel; pegaspargase; peliomycin;pentamustine; peplomycin sulfate; perfosfamide; pipobroman; piposulfan;piroxantrone hydrochloride; plicamycin; plomestane; porfimer sodium;porfiromycin; prednimustine; procarbazine hydrochloride; puromycin;puromycin hydrochloride; pyrazofurin; riboprine; rogletimide; safingol;safingol hydrochloride; semustine; simtrazene; sparfosate sodium;sparsomycin; spirogermanium hydrochloride; spiromustine; spiroplatin;streptonigrin; streptozocin; sulofenur; talisomycin; tecogalan sodium;tegafur; teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosinie sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; zorubicinhydrochloride. Other anti-cancer drugs include, but are not limited to:20-epi-1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone;aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TKantagonists; altretamine; ambamustine; amidox; amifostine;aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole;andrographolide; angiogenesis inhibitors; antagonist D; antagonist G;antarelix; anti-dorsalizing morphogenetic protein-1; antiandrogen,prostatic carcinoma; antiestrogen; antineoplaston; antisenseoligonucleotides; aphidicolin glycinate; apoptosis gene modulators;apoptosis regulators; apurinic acid; ara-CDP-DL-PTBA; argininedeaminase; asulacrine; atamestane; atrimustine; axinastatin 1;axinastatin 2; axinastatin 3; azasetron; azatoxin; azatyrosine; baccatinIII derivatives; balanol; batimastat; BCR/ABL antagonists;benzochlorins; benzoylstaurosporine; beta lactam derivatives;beta-alethine; betaclamycin B; betulinic acid; bFGF inhibitor;bicalutamide; bisantrene; bisaziridinylspermine; bisnafide; bistrateneA; bizelesin; breflate; bropirimine; budotitane; buthionine sulfoximine;calcipotriol; calphostin C; camptothecin derivatives; canarypox IL-2;capecitabine; carboxamide-amino-triazole; carboxyamidotriazole; CaRestM3; CARN 700; cartilage derived inhibitor; carzelesin; casein kinaseinhibitors (ICOS); castanospermine; cecropin B; cetrorelix; chlorlns;chloroquinoxaline sulfonamide; cicaprost; cis-porphyrin; cladribine;clomifene analogues; clotrimazole; collismycin A; collismycin B;combretastatin A4; combretastatin analogue; conagenin; crambescidin 816;crisnatol; cryptophycin 8; cryptophycin A derivatives; curacin A;cyclopentanathraquinones; cycloplatam; cypemycin; cytarabine ocfosfate;cytolytic factor; cytostatin; dacliximab; decitabine; dehydrodidemnin B;deslorelin; dexamethasone; dexifosfamide; dexrazoxane; dexverapamil;diaziquone; didemnin B; didox; diethylnorspermine;dihydro-5-azacytidine; dihydrotaxol, 9-; dioxamycin; diphenylspiromustine; docetaxel; docosanol; dolasetron; doxifluridine;droloxifene; dronabinol; duocarmycin SA; ebselen; ecomustine;edelfosine; edrecolomab; eflornithine; elemene; emitefur; epirubicin;epristeride; estramustine analogue; estrogen agonists; estrogenantagonists; etanidazole; etoposide phosphate; exemestane; fadrozole;fazarabine; fenretinide; filgrastim; finasteride; flavopiridol;flezelastine; fluasterone; fludarabine; fluorodaunorunicinhydrochloride; forfenimex; formestane; fostriecin; fotemustine;gadolinium texaphyrin; gallium nitrate; galocitabine; ganirelix;gelatinase inhibitors; gemcitabine; glutathione inhibitors; hepsulfam;heregulin; hexamethylene bisacetamide; hypericin; ibandronic acid;idarubicin; idoxifene; idramantone; ilmofosine; ilomastat;imidazoacridones; imiquimod; immunostimulant peptides; insulin-likegrowth factor-I receptor inhibitor; interferon agonists; interferons;interleukins; iobenguane; iododoxorubicin; ipomeanol, 4-; iroplact;irsogladine; isobengazole; isohomohalicondrin B; itasetron;jasplakinolide; kahalalide F; lamellarin-N triacetate; lanreotide;leinamycin; lenograstim; lentinan sulfate; leptolstatin; letrozole;leukemia inhibiting factor; leukocyte alpha interferon;leuprolide+estrogen+progesterone; leuprorelin; levamisole; liarozole;linear polyamine analogue; lipophilic disaccharide peptide; lipophilicplatinum compounds; lissoclinamide 7; lobaplatin; lombricine;lometrexol; lonidamine; losoxantrone; lovastatin; loxoribine;lurtotecan; lutetium texaphyrin; lysofylline; lytic peptides;maitansine; mannostatin A; marimastat; masoprocol; maspin; matrilysininhibitors; matrix metalloproteinase inhibitors; menogaril; merbarone;meterelin; methioninase; metoclopramide; MIF inhibitor; mifepristone;miltefosine; mirimostim; mismatched double stranded RNA; mitoguazone;mitolactol; mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; monoclonalantibody, human chorionic gonadotrophin; monophosphoryl lipidA+myobacterium cell wall sk; mopidamol; multiple drug resistance geneinhibitor; multiple tumor suppressor 1-based therapy; mustard anticanceragent; mycaperoxide B; mycobacterial cell wall extract; myriaporone;N-acetyldinaline; N-substituted benzamides; nafarelin; nagrestip;naloxone+pentazocine; napavin; naphterpin; nartograstim; nedaplatin;nemorubicin; neridronic acid; neutral endopeptidase; nilutamide;nisamycin; nitric oxide modulators; nitroxide antioxidant; nitrullyn;O6-benzylguanine; octreotide; okicenone; oligonucleotides; onapristone;ondansetron; ondansetron; oracin; oral cytokine inducer; ormaplatin;osaterone; oxaliplatin; oxaunomycin; paclitaxel; paclitaxel analogues;paclitaxel derivatives; palauamine; palmitoylrhizoxin; pamidronic acid;panaxytriol; panomifene; parabactin; pazelliptine; pegaspargase;peldesine; pentosan polysulfate sodium; pentostatin; pentrozole;perflubron; perfosfamide; perillyl alcohol; phenazinomycin;phenylacetate; phosphatase inhibitors; picibanil; pilocarpinehydrochloride; pirarubicin; piritrexim; placetin A; placetin B;plasminogen activator inhibitor; platinum complex; platinum compounds;platinum-triamine complex; porfimer sodium; porfiromycin; prednisone;propyl bis-acridone; prostaglandin J2; proteasome inhibitors; proteinA-based immune modulator; protein kinase C inhibitor; protein kinase Cinhibitors, microalgal; protein tyrosine phosphatase inhibitors; purinenucleoside phosphorylase inhibitors; purpurins; pyrazoloacridine;pyridoxylated hemoglobin polyoxyethylene conjugate; raf antagonists;raltitrexed; ramosetron; ras farnesyl protein transferase inhibitors;ras inhibitors; ras-GAP inhibitors; retelliptine demethylated; rheniumRe 186 etidronate; rhizoxin; ribozymes; RII retinamide; rogletimide;rohitukine; romurtide; roquinimex; rubiginone B1; ruboxyl; safingol;saintopin; SarCNU; sarcophytol A; sargramostim; Sdi 1 mimetics;semustine; senescence derived inhibitor 1; sense oligonucleotides;signal transduction inhibitors; signal transduction modulators; singlechain antigen binding protein; sizofiran; sobuzoxane; sodiumborocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stem cell inhibitor; stem-celldivision inhibitors; stipiamide; stromelysin inhibitors; sulfinosine;superactive vasoactive intestinal peptide antagonist; suradista;suramin; swainsonine; synthetic glycosaminoglycans; tallimustine;tamoxifen methiodide; tauromustine; tazarotene; tecogalan sodium;tegafur; tellurapyrylium; telomerase inhibitors; temoporfin;temozolomide; teniposide; tetrachlorodecaoxide; tetrazomine;thaliblastine; thiocoraline; thrombopoetin; thrombopoetin mimetic;thymalfasin; thymopoietin receptor agonist; thymotrinan; thyroidstimulating hormone; tin ethyl etiopurpurin; tirapazamine; titanocenebichloride; topsentin; toremifene; totipotent stem cell factor;translation inhibitors; tretinoin; triacetyluridine; triciribine;trimetrexate; triptorelin; tropisetron; turosteride; tyrosine kinaseinhibitors; tyrphostins; UBC inhibitors; ubenimex; urogenitalsinus-derived growth inhibitory factor; urokinase receptor antagonists;vapreotide; variolin B; vector system, erythrocyte gene therapy;velaresol; veramine; verdins; verteporfin; vinorelbine; vinxaltine;vitaxin; vorozole; zanoterone; zeniplatin; zilascorb; and zinostatinstimalamer.

[0131] The compounds of the present invention and the other therapeuticagent can act additively or, more preferably, synergistically. In apreferred embodiment, a composition comprising a compounds of thepresent invention is administered concurrently with the administrationof another therapeutic agent, which can be part of the same compositionor in a different composition from that comprising the compounds of thepresent invention. In another embodiment, a composition comprising thecompounds of the present invention is administered prior to orsubsequent to administration of another therapeutic agent.

[0132] The compounds of the present invention when administered, e.g.,via the oral, parenteral or topical routes to mammals, can be in adosage in the range of about 0.01 mg/kg to about 3000 mg/kg body weightof the patient per day, preferably about 0.01 mg/kg to about 1000 mg/kgbody weight per day administered singly or as a divided dose. However,variations will necessarily occur depending upon the weight and physicalcondition (e.g., hepatic and renal function) of the subject beingtreated, the affliction to be treated, the severity of the symptoms, theroute of administration, the frequency of the dosage interval, thepresence of any deleterious side-effects, and the particular compoundutilized, among other things.

[0133] The compounds of the present invention preferably have a bindingaffinity K_(i) for the human ORL-1 receptor of about 500 nM or less; 100nM or less; 50 nM or less; 20 nM or less or 5 nM or less. The bindingaffinity K_(i) can be measured by one skilled in the art by an assayutilizing membranes from recombinant HEK-293 cells expressing the humanopioid receptor-like receptor (ORL-1) as described below.

[0134] The following examples illustrate various aspects of the presentinvention, and are not to be construed to limit the claims in any mannerwhatsoever.

EXAMPLE 1 Synthesis of Spirocyclic Head Groups

[0135]

Procedure

[0136] To a solution of freshly prepared LDA in THF (1.1 eq) at −40° C.was added a solution of 1 (1 eq) in THF. The reaction mixture wasallowed to warm to RT and stir for 1 hr. After cooling to −20° C., asolution of benzoyl chloride (2, 1.2 eq) in THF was added dropwise.After stirring at −20° C. for 1 hr and at RT for 16 hr, the reactionmixture was poured into water and extracted with ethyl acetate. Theorganic extracts were washed with saturated ammonium chloride, brine,dried over MgSO₄, filtered and the solvent evaporated to give crude 3 asan oil, which was used without purification in the next step.

[0137]¹H-NMR (CDCl₃): d 1.08 (t, 3H), 2.28 (t, 4H), 2.43 (m, 2H), 2.54(m, 2H), 3.46 (s, 2H), 4.13 (q, 2H), 7.21-7.31 (m, 5H), 7.39 (m, 2H),7.49 (m, 1H), 7.79 (m, 2H).

[0138] To a solution of 3 (1 eq) in ethanol was added hydrazine hydrate(3 eq). After refluxing for 12 hr, the reaction mixture was cooled to RTand the crude product filtered. The solid was recrystalized from ethanolto give 4 as a white solid.

[0139]¹H-NMR (DMSO): d 1.67 (d, 2H), 2.23 (dt, 2H), 2.62 (dd, 2H), 2.83(dt, 2H), 3.56 (s, 2H), 7.25 (m, 1H), 7.35 (m, 4H), 7.50 (m, 3H), 7.78(m, 2H).

[0140] Compound 4 (1 eq) and Pd(OH)₂ (0.2 eq) in methanol washydrogenated at RT and 50 psi of hydrogen for 20 hr. Filtration andevaporation gave crude 5. Recrystalization from ethanol gave pule 5 as awhite solid.

[0141]¹H-NMR (DMSO): d 1.50 (d, 2H), 2.12 (m, 2H), 2.73 (m, 2H), 3.28(m, 2H), 7.45 (m, 3H), 7.86 (d, 2H).

EXAMPLE 2 Attachment of Tail Groups

[0142] Tail groups were attached to the head groups according to thefollowing procedures:

General Procedure for Alkylation

[0143] To a solution of the amine (1 eq) and triethylamine (1 eq) indimethylformamide, was added 1 eq of alkyl bromide or chloride in oneportion. The mixture was stirred and heated at 80° C. over night. TLCindicated the reaction was complete. The reaction was quenched by theaddition of water followed by 1 N NaOH to pH 10. The mixture wasextracted 2× with Et₂O. The combined organic extracts were dried overpotassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

General Procedure for Reductive Animation

[0144] To a mixture of ketone or aldehyde (1 eq), amine (1 eq), andacetic acid (1 eq) in methanol, was added sodium cyanoborohydride (1.4eq) in one portion. The mixture was stirred over night at roomtemperature. TLC indicated the reaction was complete. The reaction wasquenched by the addition of water followed by 1 N NaOH to pH 10. Themixture was extracted 2× with Et₂O. The combined organic extracts weredried over potassium carbonate and the solvent evaporated, followed bychromatography to give the pure product.

[0145] The following compounds were prepared by attaching the tailgroups using the general procedures described:

8-(benzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0146] MS: m/z 342.2 (M+Na). ¹H-NMR (DMSO): d 1.67 (d, 2H), 2.23 (dt,2H), 2.62 (dd, 2H), 2.83 (dt, 2H), 3.56 (s, 2H), 7.25 (m, 1H), 7.35 (m,4H), 7.50 (m, 3H), 7.78 (m, 2H).

8-[(naphth-2-yl-methyl)]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0147] LC: 97.7%. MS: m/z 370.6 (M+1). ¹H-NMR (CDCl₃): d 1.80 (b, 2H),2.50 (m, 2H), 2.80 (b, 2H), 2.03 (t, 2H), 3.75 (s, 2H), 7.50 (m, 5H),7.60 (d, 1H), 7.80 (m, 6H), 8.42 (b, 1H).

8-(p-phenylbenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0148] LC: 90.1%. MS: m/z 396.6 (M+1). ¹H-NMR (CDCl₃): d 1.80 (b, 2H),2.51 (m, 2H), 2.80 (b, 2H), 3.02 (m, 2H), 3.75 (s, 2H), 7.35-7.70 (m,12H), 7.85 (b, 2H), 8.50 (b, 1H).

8-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0149] LC: 100%. MS: m/z 444.2 (M+Na). ¹H-NMR (CDCl₃):. d 1.75 (b, 2H),2.35 (m, 2H), 2.61 (b, 2H), 2.85 (m, 4H), 4.11 (m, 2H), 4.20 (s, 1H),7.10-7.28 (m, 8H), 7.45 (m, 3H), 7.85 (m, 2H), 8.5 (s, 1H).

8-[4,4-Bis(4-fluorophenyl)butyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0150] LC: 96.9%. MS: m/z. ¹-NMR (CDCl₃): d 0.75-2.90 (m, 10H), 3.60 (m,2H), 3.80 (m, 1H), 3.90 (m, 1H), 4.55 (m, 1H), 6.90-7.50 (m, 11H), 7.80(b, 2H), 8.45 (b, 1H).

8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0151] LC: 100%. MS: m/z 424.2 (M+1). ¹H-NMR (CDCl₃): d 1.80 (b, 2H),2.35 (m, 2H), 2.50 (m, 4H), 2.78 (b, 2H), 2.95 (m, 2H), 4.05 (t, 1H),7.20 (m, 2H), 7.30 (m, 8H), 7.45 (m, 3H), 7.85 (b, 2H), 8.70 (b, 1H).

8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0152] LC: 97.6%. MS: m/z 426.2. ¹H-NMR (CDCl₃): d 1.80 (b, 2H), 2.45(dt, 2H), 2.80 (b, 2H), 2.95 (m, 2H), 3.60 (s, 2H), 5.10 (s, 2H), 6.95(d, 2H), 7.30-7.50 (m, 10H), 7.88 (m, 2H), 8.71 (s, 1H).

8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0153] LC: 95.3%. MS: m/z 360.2 (M+1). ¹H-NMR(CDCl₃): d 1.85-1.90 (m,3H), 2.42 (b, 1H), 2.85-3.15 (m, 6H), 3.20 (b, 2H), 3.40 (m, 2H), 3.75(m, 1H), 7.10-7.20 (m, 4H), 7.50 (m, 3H), 8.00 (d, 2H).

8-(4-propylcyclohexyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0154] LC: 100%. MS: m/z 354.2 (M+1). ¹H-NMR (CDCl₃): d 1.95 (t, 3H),1.35 (m, 6H), 1.60 (m, 2H), 1.80 (m, 3H), 1.95 (d, 4H), 2.25 (d, 1H),3.05 (t, 3H), 3.30 (d, 2H), 3.8 (q. 2H), 7.50 (t, 1H), 7.60 (m, 2H),8.00 (d, 2H).

8-(5-methylhex-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0155] LC: 100%. MS: m/z 328.2 (M+1). ¹H-NMR (CDCl₃): d 0.9-1.65 (m,12H), 2.00 (bd, 4H), 2.05-2.30 (m, 5H), 3.95 (t, 2H), 7.50 (t, 1H), 7.60(t, 2H), 8.02 (d, 2H).

8-norbornyl-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0156] MS: m/z 324.2 (M+1). ¹H-NMR (CDCl₃): d 0.80-3.90 (m, 16H), 4.20(m, 2H), 4.85 (b, 1H), 7.40-7.62 (m, 3H), 8.05 (m, 2H), 8,75 (b, 1H).

8-(decahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0157] LC: 100%. MS: m/z 366.2 (M+1). ¹H-NMR (CDCl₃): d 0.95-2.15 (m,17H), 2.30 (m, 1H), 3.10 (m, 3H), 3.35 (m, 2H), 3.95 (m, 2H), 7.55 (t,1H), 7.65 (t, 2H), 8.02 (d, 2H).

8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0158] LC: 100%. MS: m/z 340.2 (M+1). ¹H-NMR (CDCl₃): d 1.40-2.25 (m,16H), 3.10 (m, 2H), 3.20 (b, 2H), 3.38 (m, 1H), 4.02 (m, 2H), 7.50 (t,1H), 7.60 (t, 2H), 8.02 (m, 2H).

8-[4-(2-propyl)-cyclohexyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0159] LC: 100%. MS: m/z 354.2 (M+1). ¹H-NMR (CDCl₃): d 0.9 (m, 6H),1.45-1.65 (m, 3H), 1.78 (m, 2H), 2.00 (b, 6H), 2.30 (d, 1H), 3.10 (m,3H), 3.30 (t, 2H), 3.95 (q, 2H), 7.50 (t, 1H), 7.60 (t, 2H), 8.00 (m,2H).

8-(1,3-dihydroinden-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0160] LC: 100%. MS: m/z 346.1 (M+1). ¹H-NMR (CDCl₃): d 1.90-3.80 (m,12H), 4.25 (m, 1H), 7.20-7.70 (m, 8H), 7.95 (d, 1H).

8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0161] LC: 92.9%. MS: m/z 354.6 (M+1). ¹H-NMR (MeOH): d 1.40-1.80 (m,14H), 2.00 (b, 2H), 2.10 (m, 1H), 2.60 (m, 2H), 2.90 (m, 2H), 3.40 (m,2H), 3.70 (m, 2H), 7.50 (m, 3H), 7.80.

8-(acenaphthen-9-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one

[0162] LC: 100%. MS: m/z 382.2 (M+1). ¹H-NMR (CDCl₃): 1.69 (dd, 1H),1.72 (dd, 1H), 2.36-2.44 (m, 2H), 2.52-2.60 (ddd, 1H), 2.83 (brd, 1H),3.17-3.24 (m, 1H), 3.30-3.44 (m, 2H), 3.60-3.65 (m, 1H), 5.01 (dd, 1H),7.31 (d, 1H), 7.45-7.49 (m, 4H), 7.52-7.57 (m, 2H), 7.62-7.64 (d, 1H),7.69-7.71 (m, 1H), 7.86-7.88 (m, 2H), 8.42 (s, 1H).

[0163] Other compounds within the scope of formula (I) or (IA) of thepresent invention can be synthesized by analogous techniques.

EXAMPLE 3

[0164] Nociceptin affinity at the ORL1 receptor for preferred compoundswas obtained using the following assay:

[0165] Membranes from recombinant HEK-293 cells expressing the humanopioid receptor-like receptor (ORL-1) (Receptor Biology) were preparedby lysing cells in ice-cold hypotonic buffer (2.5 mM MgCl₂, 50 mM HEPES,pH 7.4) (10 ml/10 cm dish) followed by homogenization with a tissuegrinder/teflon pestle. Membranes were collected by centrifugation at30,000×g for 15 min at 4° C. and pellets resuspended in hypotonic bufferto a final concentration of 1-3 mg/ml. Protein concentrations weredetermined using the BioRad protein assay reagent with bovine serumalbumen as standard. Aliquots of the ORL-1 receptor membranes werestored at −80° C.

[0166] Functional SGTPgS binding assays were conducted as follows. ORL-1membrane solution was prepared by sequentially adding finalconcentrations of 0.066 mg/ml ORL-1 membrane protein, 10 mg/ml saponin,3 mM GDP and 0.20 nM [³⁵S]GTPgS to binding buffer (100 mM NaCl, 10 mMMgCl₂, 20 mM HEPES, pH 7.4) on ice. The prepared membrane solution (190ml/well) was transferred to 96-shallow well polypropylene platescontaining 10 ml of 20× concentrated stock solutions of agonist preparedin DMSO. Plates were incubated for 30 min at room temperature withshaking. Reactions were terminated by rapid filtration onto 96-wellUnifilter GF/B filter plates (Packard) using a 96-well tissue harvester(Brandel) and followed by three filtration washes with 200 ml ice-coldbinding buffer (10 mM NaH₂PO₄, 10 mM Na₂HPO₄, pH 7.4). Filter plateswere subsequently dried at 50° C. for 2-3 hours. Fifty ml/wellscintillation cocktail (BetaScint; Wallac) was added and plates werecounted in a Packard Top-Count for 1 min/well.

[0167] Data was analyzed using the curve fitting functions in GraphPadPRISMÔ, v. 3.0 and the results are set forth in table 1 below: TABLE 1Nociceptin Affinity calc K_(i) Compound (nM)8-(4-propylcyclohexyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4- 29.7 one8-(5-methylhex-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 11.58-norbornyl-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 8978-(decahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan- 1.1 4-one8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 8.18-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8- 52.3triazospiro[4.5]decan-4-one 8-[4-(2-propyl)-cyclohexyl]-1-phenyl-2,3,8-1.5 triazospiro[4.5]decan-4-one8-(1,3-dihydroinden-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan- 43 4-one8-[(naphth-2-yl-methyl)]-1-phenyl-2,3,8-triazospiro[4.5]decan-4- 402 one8-(p-phenylbenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 71718-[4,4-Bis(4-fluorophenyl)butyl]-1-phenyl-2,3,8- 2589triazospiro[4.5]decan-4-one8-(benzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 2938-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-1-phenyl- 2822,3,8-triazospiro[4.5]decan-4-one8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-triazospiro[4.5]decan- 75 4-one8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4- 138 one8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 618-(acenaphthen-9-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one .06

EXAMPLE 5

[0168] Affinity at the μ receptor for compounds was obtained accordingto the following assay:

[0169] Mu opioid receptor membrane solution was prepared by sequentiallyadding final concentrations of 0.075 μg/μl of the desired membraneprotein, 10 μg/ml saponin, 3 μM GDP and 0.20 nM [³⁵S]GTPγS to bindingbuffer (100 mM NaCl, 10 mM MgCl₂, 20 mM HEPES, pH 7.4) on ice. Theprepared membrane solution (190 μl/well) was transferred to 96-shallowwell polypropylene plates containing 10 μl of 20× concentrated stocksolutions of agonist prepared in DMSO. Plates were incubated for 30 minat room temperature with shaking. Reactions were terminated by rapidfiltration onto 96-well Unifilter GF/B Filter plates (Packard) using a96-well tissue harvester (Brandel) and followed by three filtrationwashes with 200 μl ice-cold binding buffer (10 mM NaH₂PO₄, 10 mMNa₂HPO₄, pH 7.4). Filter plates were subsequently dried at 50° C. for2-3 hours. Fifty μl/well scintillation cocktail (MicroScint20, Packard)was added and plates were counted in a Packard Top-Count for 1 min/well.

[0170] Data were analyzed using the curve fitting functions in GraphPadPRISM™, v.3.0 and the results for several compounds are set forth intable 2 below: TABLE 2 Mu Receptor Affinity calc K_(i) Compound (nM)8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8- 115triazospiro[4.5]decan-4-one8-[(naphth-2-yl-methyl)]-1-phenyl-2,3,8-triazospiro[4.5]decan- 84 4-one8-(benzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 568-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one 191

What is claimed is:
 1. A compound of formula (I):

wherein W is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₃₋₁₂cycloalkylC₁₋₄alkyl-, C₁₋₁₀ alkoxy, C₃₋₁₂ cycloalkoxy-, C₁₋₁₀ alkylsubstituted with 1-3 halogen, C₃₋₁₂ cycloalkyl substituted with 1-3halogen, C₃₋₁₂ cycloalkylC₁₋₄alkyl-substituted with 1-3 halogen, C₁₋₁₀alkoxy substituted with 1-3 halogen, C₃₋₁₂ cycloalkoxy-substituted with1-3 halogen, —COOV₁, —C₁₋₄COOV₁, —CH₂OH, —SO₂N(V₁)₂, hydroxyC₁₋₁₀alkyl-,hydroxyC₃₋₁₀cycloalkyl-, cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-,—CON(V₁)₂, NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, sulfonylaminoC₁₋₁₀alkyl-,diaminoalkyl-, -sulfonylC₁₋₄alkyl, a 6-membered heterocyclic ring, a6-membered heteroaromatic ring, a 6-membered. heterocyclicC₁₋₄alkyl-, a6-membered heteroaromaticC₁₋₄alkyl-, a 6-membered aromatic ring, a6-membered aromaticC₁₋₄ alkyl-, a 5-membered heterocyclic ringoptionally substituted with an oxo or thio, a 5-membered heteroaromaticring, a 5-membered heterocyclicC₁₋₄alkyl-optionally substituted with anoxo or thio, a 5-membered heteroaromaticC₁₋₄alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅(═NH)W₁, —C₁₋₅NHC(═O)W₁, —C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, whereinW₁ is hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy, C₃₋₁₂cycloalkoxy, —CH₂OH, amino, C₁₋₄alkylamino-, diC₁₋₄alkylamino-, or a5-membered heteroaromatic ring optionally substituted with 1-3 loweralkyl; wherein each V₁ is independently selected from H, C₁₋₆ alkyl,C₃₋₆ cycloalkyl, benzyl or phenyl Q is a C₁₋₈ alkyl, 5-8 memberedcycloalkyl, 5-8 membered heterocyclic or a 6 membered aromatic orheteroaromatic group; n is an integer from 0 to 3; A, B and C areindependently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl, C₁₋₁₀ alkoxy,C₃₋₁₂ cycloalkoxy, —CH₂OH, —NHSO₂, hydroxyC₁₋₁₀alkyl-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-, acylamino-,acylaminoalkyl-, amide, sulfonylaminoC₁₋₁₀alkyl-, or A-B can togetherform a C₂₋₆ bridge, or B—C can together form a C₃₋₇ bridge, or A-C cantogether form a C₁₋₅ bridge; Z is selected from the group consisting ofa bond, straight or branched C₁₋₆ alkylene, —NH—, —CH₂O—, —CH₂NH—,—CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH2CO—, —COCF₂—,—CH₂COCH₂—, —CH(CH₃)—, —CH═, —O— and —HC═CH—, wherein the carbon and/ornitrogen atoms are unsubstituted or substituted with one or more loweralkyl, hydroxy, halo or alkoxy group; R₁ is selected from the groupconsisting of hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl,amino, C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, —COOV₁, —C₁₋₄COOV₁,cyano, cyanoC₁₋₁₀alkyl-, cyanoC₃₋₁₀cycloalkyl-, NH₂SO₂—,NH₂SO₂C₁₋₄alkyl-, NH₂SOC₁₋₄alkyl-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, diC₁₋₄alkylaminocarbonyl-, benzyl, C₃₋₁₂cycloalkenyl-, a monocyclic, bicyclic or tricyclic aryl or heteroarylring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and aspiro ring system of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; and wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino-, C₃₋₁₂cycloalkylamino-, or benzyl of R₁ is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, hydroxy, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl-,cyano, —COOV₁, —C₁₋₄COOV₁, cyanoC₁₋₁₀alkyl-, —C₁₋₅(═O)W₁,—C₁₋₅NHS(═O)₂W₁, —C₁₋₅NHS(═O)W₁, a 5-membered heteroaromaticC₀₋₄alkyl-,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl-, C₁₋₁₀ alkoxy-, and cyano; andwherein'said C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclicor tricyclic aryl, heteroaryl ring, hetero-monocyclic ring,hetero-bicyclic ring system, or spiro ring system of the formula (II) isoptionally substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀alkoxy, nitro,trifluoromethyl-, phenyl, benzyl, phenyloxy and benzyloxy, wherein saidphenyl, benzyl, phenyloxy or benzyloxy is optionally substituted with1-3 substituents selected from the group consisting of halogen, C₁₋₁₀alkyl, C₁₋₁₀ alkoxy, and cyano; R₂ is selected from the group consistingof hydrogen, C₁₋₁₀ alkyl, C₃₋₁₂ cycloalkyl and halogen, said alkyl orcycloalkyl optionally substituted with an oxo, amino, alkylamino ordialkylamino group; or a pharmaceutically acceptable salt thereof orsolvate thereof.
 2. A compound of claim 1, wherein Q is phenyl or a 6membered heteroaromatic group containing 1-3 nitrogen atoms.
 3. Acompound of claim 1, wherein W is selected from the group consisting of—CH₂C═ONH₂, —C(NH)NH₂, pyridylmethyl, cyclopentyl, cyclohexyl,furanylmethyl, —C═OCH₃, —CH₂CH₂NHC═OCH₃, —SO₂CH₃, CH₂CH₂NHSO₂CH₃,furanylcarbonyl-, methylpyrrolylcarbonyl-, diazolecarbonyl-,azolemethyl-, trifluoroethyl-, hydroxyethyl-, cyanomethyl-,oxo-oxazolemethyl-, and diazolemethyl-.
 4. A compound of claim 1,wherein ZR₁ is selected from the group consisting of cyclohexylethyl-,cyclohexylmethyl-, cyclopentylmethyl-, dimethylcyclohexylmethyl-,phenylethyl-, pyrrolyltrifluoroethyl-, thienyltrifluoroethyl-,pyridylethyl-, cyclopentyl-, cyclohexyl-, methoxycyclohexyl-,tetrahydropyranyl-, propylpiperidinyl-, indolylmethyl-, pyrazoylpentyl-,thiazolylethyl-, phenyltrifluoroethyl-, hydroxyhexyl-, methoxyhexyl-,isopropoxybutyl-, hexyl-, and oxocanylpropyl-.
 5. A compound of claim 1,wherein at least one of ZR₁ or W is selected from the group consistingof CH₂COOV₁, tetrazolylmethyl-, cyanomethyl-, NH₂SO₂methyl-,NH₂SOmethyl-, aminocarbonylmethyl-, C₁₋₄alkylaminocarbonylmethyl-, anddiC₁₋₄alkylaminocarbonylmethyl-.
 6. A compound of claim 1, wherein ZR₁is 3,3 diphenylpropyl optionally substituted at the 3 carbon of thepropyl with —COOV₁, tetrazolylC₀₋₄alkyl-, cyano-, aminocarbonyl-,C₁₋₄alkylaminocarbonyl-, or diC₁₋₄alkylaminocarbonyl-.
 7. A compound offormula (IA):

wherein n is an integer from 0 to 3; Z is selected from the groupconsisting of a bond, —CH₂—, —NH—, —CH₂O—, —CH₂CH₂—, —CH₂NH—,—CH₂N(CH₃)—, —NHCH₂—, —CH₂CONH—, —NHCH₂CO—, —CH₂CO—, —COCH₂—,—CH₂COCH₂—, —CH(CH₃)—, —CH═, and —HC═CH—, wherein the carbon and/ornitrogen atoms are unsubstituted or substituted with a lower alkyl,halogen, hydroxy or alkoxy group; R₁ is selected from the groupconsisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂cycloalkyl, C₂₋₁₀alkenyl,amino, C₁₋₁₀alkylamino, C₃₋₁₂cycloalkylamino, benzyl, C₃₋₁₂cycloalkenyl, a monocyclic, bicyclic or tricyclic aryl or heteroarylring, a hetero-monocyclic ring, a hetero-bicyclic ring system, and aspiro ring system of the formula (II):

wherein X₁ and X₂ are independently selected from the group consistingof NH, O, S and CH₂; wherein said alkyl, cycloalkyl, alkenyl,C₁₋₁₀alkylamino, C₃₋₁₂cycloalkylamino, or benzyl is optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl, cyano,phenyl, benzyl, benzyloxy, said phenyl, benzyl, and benzyloxy optionallybeing substituted with 1-3 substituents selected from the groupconsisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, and cyano; whereinsaid C₃₋₁₂ cycloalkyl, C₃₋₁₂ cycloalkenyl, monocyclic, bicyclic ortricyclic aryl, heteroaryl ring, hetero-monocyclic ring, hetero-bicyclicring system, and spiro ring system of the formula (II) are optionallysubstituted with 1-3 substituents selected from the group consisting ofhalogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, nitro, trifluoromethyl, phenyl,benzyl, phenyloxy and benzyloxy, wherein said phenyl, benzyl, phenyloxyand benzyloxy are optionally substituted with 1-3 substituents selectedfrom the group consisting of halogen, C₁₋₁₀ alkyl, C₁₋₁₀ alkoxy, andcyano; R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl and halogen, said alkyl optionally substitutedwith an oxo group; or a pharmaceutically acceptable salt thereof.
 8. Acompound of claim 7, wherein R₁ is alkyl selected from the groupconsisting of methyl, ethyl, propyl, butyl, pentyl and hexyl.
 9. Acompound of claim 7, wherein R₁ is cycloalkyl selected from the groupconsisting of cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl,cyclodecyl, and norbornyl.
 10. A compound of claim 7, wherein R₁ istetrahydronaphthyl, decahydronaphthyl or dibenzocycloheptyl.
 11. Acompound of claim 7, wherein R₁ is phenyl or benzyl.
 12. A compound ofclaim 7, wherein R₁ is a bicyclic aromatic ring.
 13. A compound of claim12, wherein said bicyclic aromatic ring is indenyl, quinoline ornaphthyl.
 14. A compound of claim 7, wherein Z is a bond, methyl, orethyl.
 15. A compound of claim 7, wherein n is
 0. 16. A compound ofclaim 7, wherein X₁ and X₂are both O.
 17. A compound selected from thegroup consisting of8-(4-propylcyclohexyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(5-methylhex-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-norbornyl-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(decahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(1,2,3,4-tetrahydro-2-naphthyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-[4-(2-propyl)-cyclohexyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(1,3-dihydroinden-2-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-[(naphth-2-yl-methyl)]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(p-phenylbenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-[4,4-Bis(4-fluorophenyl)butyl]-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(benzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(10,11-Dihydro-5H-dibenzo[a,d]-cyclohepten-5-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(3,3-Bis(phenyl)propyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(p-benzyloxybenzyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one;8-(cyclooctylmethyl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one; andpharmaceutically acceptable salts thereof
 18. A compound which is8-(acenaphthen-9-yl)-1-phenyl-2,3,8-triazospiro[4.5]decan-4-one or apharmaceutically acceptable salt thereof or solvate thereof.
 19. Apharmaceutical composition comprising a compound of claim 1 and at leastone pharmaceutically acceptable excipient.
 20. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 1. 21. A method ofmodulating a pharmacological response from the ORL1 receptor comprisingadministering to a patient in need thereof an effective amount of acompound according to claim
 1. 22. A pharmaceutical compositioncomprising a compound of claim 7 and at least one pharmaceuticallyacceptable excipient.
 23. A method of treating pain comprisingadministering to a patient in need thereof, an effective amount of ananalgesic compound according to claim
 7. 24. A method of modulating apharmacological response from the ORL1 receptor comprising administeringan effective amount of a compound according to claim
 7. 25. A compoundof formula (IA):

wherein R₂ is selected from the group consisting of hydrogen, C₁₋₁₀alkyl, C₃₋₁₂ cycloalkyl and halogen; said alkyl optionally substitutedwith an oxo group; n is an integer from 0 to 3; and ZR₁ is

wherein Y₁ is R₃—(C₁-C₁₂)alkyl, R₄-aryl, R₅-heteroaryl,R₆—(C₃-C₁₂)cyclo-alkyl, R₇—(C₃-C₇)heterocycloalkyl, —CO₂(C₁-C₆)alkyl, CNor —C(O)NR₈R₉; Y₂ is hydrogen or Y₁; Y₃ is hydrogen or (C₁-C₆)alkyl; orY₁, Y₂ and Y₃, together with the carbon to which they are attached, formone of the following structures:

wherein r is 0 to 3; w and u are each 0-3, provided that the sum of wand u is 1-3; c and d are independently 1 or 2; s is 1 to 5; and ring Eis a fused R₄-phenyl or R₅-heteroaryl ring; R₁₀ is 1 to 3 substituentsindependently selected from the group consisting of H, (C₁-C₆)alkyl,—OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ and —(C₁-C₆)alkyl-NR₈R₉; R₁₁ is 1 to 3substituents independently selected from the group consisting of R₁₀,—CF₃, —OCF₃, NO₂ and halo, or R₁₁ substituents on adjacent ring carbonatoms may together form a methylenedioxy or ethylenedioxy ring;. R₈ andR₉ are independently selected from the group consisting of hydrogen,(C₁-C₆) alkyl, (C₃-C₁₂)cycloalkyl, aryl and aryl(C₁-C₆)alkyl; R₃ is 1 to3 substituents independently selected from the group consisting of H,R₄-aryl, R₆—(C₃-C₁₂)cycloalkyl, R₅-heteroaryl,R₇—(C₃-C₇)heterocycloalkyl, —NR₈ R₉, —OR₁₂ and —S(O)₀₋₂R₁₂; R₆ is 1 to 3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, R₄-aryl, —NR₈R₉, —OR₁₂ and —SR₁₂; R₄ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆ )alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —SO₂R₈, —SOR₈, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈, —COCF₃,—OCOR₈, —OCO₂R₈, —COOR₈, —(C₁-C₆)alkyl-NHCOOC(CH₃)₃,—(C₁-C₆)alkyl-NHCOCF₃, —(C₁-C₆)alkyl-NHSO₂—(C₁-C₆)alkyl,—(C₁-C₆)alkyl-NHCONH—(C₁-C₆)-alkyl and

wherein f is 0 to 6; or R₄ substituents on adjacent ring carbon atomsmay together form a methylenedioxy or ethylenedioxy ring; R₅ is 1 to 3substituents independently selected from the group consisting ofhydrogen, halo, (C₁-C₆)alkyl, R₁₃-aryl, (C₃-C₁₂)cycloalkyl, —CN, —CF₃,—OR₈, —(C₁-C₆)alkyl-OR₈, —OCF₃, —NR₈R₉, —(C₁-C₆)alkyl-NR₈R₉, —NHSO₂R₈,—SO₂N(R₁₄)₂, —NO₂, —CONR₈R₉, —NR₉COR₈, —COR₈, —OCOR₈, —OCO₂R₈ and—COOR₈; R₇ is H, (C₁-C₆)alkyl, —OR₈, —(C₁-C₆)alkyl-OR₈, —NR₈R₉ or—(C₁-C₆)alkyl-NR₈R₉; R₁₂ is H, (C₁-C₆)alkyl, R₄-aryl, —(C₁-C₆)alkyl-OR₈,—(C₁-C₆)alkyl-NR₈R₉, —(C₁-C₆)alkyl-SR₈, or aryl (C₁-C₆)alkyl; R₁₃ is 1-3substituents independently selected from the group consisting of H,(C₁-C₆)alkyl, (C₁-C₆)alkoxy and halo; R₁₄ is independently selected fromthe group consisting of H, (C₁-C₆)alkyl and R₁₃C₆H₄—CH₂—; or apharmaceutically acceptable salt thereof.
 26. A pharmaceuticalcomposition comprising a compound of claim 25 and at least onepharmaceutically acceptable excipient.
 27. A method of treating paincomprising administering to a patient in need thereof, an effectiveamount of an analgesic compound according to claim
 25. 28. A method ofmodulating a pharmacological response from the ORL1 receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 25. 29. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 1. 30. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim
 7. 31. A method of modulating apharmacological response from an opioid receptor comprisingadministering to a patient in need thereof, an effective amount of acompound according to claim 25.